X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease

X-linked lymphoproliferative disease (XLP1) is a rare immunodeficiency characterized by severe immune dysregulation and caused by mutations in the SH2D1A/SAP gene. Clinical manifestations are varied and include hemophagocytic lymphohistiocytosis (HLH), lymphoma and dysgammaglobulinemia, often triggered by Epstein-Barr virus infection. Historical data published before improved treatment regimens shows very poor outcome. We describe a large cohort of 91 genetically defined XLP1 patients collected from centers worldwide and report characteristics and outcome data for 43 patients receiving hematopoietic stem cell transplant (HSCT) and 48 untransplanted patients. The advent of better treatment strategies for HLH and malignancy has greatly reduced mortality for these patients, but HLH still remains the most severe feature of XLP1. Survival after allogeneic HSCT is 81.4% with good immune reconstitution in the large majority of patients and little evidence of posttransplant lymphoproliferative disease. However, survival falls to 50% in patients with HLH as a feature of disease. Untransplanted patients have an overall survival of 62.5% with the majority on immunoglobulin replacement therapy, but the outcome for those untransplanted after HLH is extremely poor (18.8%). HSCT should be undertaken in all patients with HLH, because outcome without transplant is extremely poor. The outcome of HSCT for other manifestations of XLP1 is very good, and if HSCT is not undertaken immediately, patients must be monitored closely for evidence of disease progression.     

Association of APOE (Hha1) and ACE (I/D) gene polymorphisms with type 2 diabetes mellitus in North West India

Familial and epidemiological studies have shown that genetic factors play a role in the development and progression of type 2 diabetes mellitus (T2DM). Asian Indians have shown an increasing prevalence of T2DM. Apolipoprotein E (APOE) and Angiotensin-1 converting enzyme (ACE) I/D polymorphisms have been associated with T2DM. This study examined the association of APOE and ACE genes with T2DM patients of Punjab, India. APOE (HhaI) and ACE (I/D) genotypes analysed by polymerase chain reaction were available from 90 patients and 97 random healthy controls. All loci and populations are in Hardy-Weinberg equilibrium. There is no significant association of APOE vis-à-vis T2DM, however APOE*4 allele frequency is low in diabetics (3.9% and 8.8%). DD genotype and *D allele of ACE are associated with T2DM (OR=1.90, p<0.05, and OR=1.58, p<0.05, respectively). Recessive and multiplicative mode of inheritance for *D allele provided the strongest support for the association. Height, weight and BMI did not reveal any significant association with APO or ACE. DD-33 and ID-23 combinations (ACE-APOE) showed higher odds of 2.01 and 2.14, respectively. ACE but not APOE polymorphism is positively associated with T2DM in Indian population, however, the synergistic effects of DD-33 and ID-23 are also evident.     

Corticotropin-releasing factor and neuropeptide Y mRNA levels are elevated in the preoptic area of socially subordinate rainbow trout

The objectives of this study were to characterize rainbow trout (Oncorhynchus mykiss) corticotropin-releasing factor (CRF) and neuropeptide Y (NPY) cDNAs and to determine their mRNA levels in response to social stress. Standard cloning techniques were used to obtain cDNAs, sequences for trout NPY and two CRF isoforms. At the predicted amino acid level, our NPY sequence differs from the trout amino acid sequence reported by. A phylogenetic analysis suggests that the two CRF isoforms result from a gene duplication that occurred in a common ancestor of salmonids. A tissue distribution demonstrated that the mRNAs of both CRF isoforms are predominantly present in the preoptic area of the trout brain, whereas NPY mRNA is more abundant in the telencephalon. Pairs of sized-matched juvenile female trout were allowed to interact for 72 h and social ranks were assigned on the basis of behavioural observations. Mean plasma cortisol levels were 13-fold higher in subordinate than in dominant trout. As measured by ribonuclease protection assay, CRF1 and NPY mRNA levels were respectively 51 and 32% higher in the preoptic area of subordinate trout; in addition, CRF1 and NPY mRNA levels were positively correlated (R2=0.44). These results suggest that subordinate rainbow trout chronically maintain high levels of CRF mRNA during social stress and that NPY may be involved in the control of the stress axis in trout.     

Frequency of the mitochondrial DNA 4977bp deletion in oesophageal mucosa during the progression of Barrett’s oesophagus

PurposeThe mechanisms of the progression of Barrett’s oesophagus (BO) to oesophageal adenocarcinoma (OA) are poorly understood. The frequency of the 4977bp deletion in mitochondrial DNA (mtDNA) was investigated in specimens ranging from normal oesophageal tissue to OA in order to investigate whether this deletion represents a useful biomarker of disease progression.MethodsThe presence of the 4977bp deletion was screened by PCR amplification from 70 specimens in total.ResultsThe frequency of specimens with the 4977bp deletion increased in relation to the degree of dysplasia (8.3% in normal squamous epithelium; 15.4% in BO; 40% in low grade dysplasia (LGD); 69.2% in high-grade dysplasia and 90% in para-tumoural tissue). However, the frequency of the deletion reduced sharply in OA specimens (16.7%; p < 0.001).ConclusionThe mtDNA 4977bp deletion may be useful as a biomarker to detect the severity of dysplasia but not the presence of OA.